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U.S. researchers have shown that
inhibiting c-Mer proto-oncogene
tyrosine kinase, a protein that sits
upstream from BRAF,
reduced melanoma growth in mice.1 Future studies will need to
determine whether inhibitors of this kinase are effective in BRAF-resistant
tumors.

Studies by multiple groups have shown that MERTK
is overexpressed or hyperactivated-and thus a potential therapeutic target-in
leukemia2 and in prostate,3 brain4 and lung5
cancers. At least one study has shown that TAM and other tyrosine kinase
receptors are activated in melanoma,6 and two more have linked
TYRO3, AXL and the TAM receptor ligand, growth
arrest-specific 6 (GAS6),
to melanoma tumorigenesis and invasiveness.7,8

Collectively, these findings prompted Douglas Graham and
colleagues to hypothesize that MERTK might also be a therapeutic target in
melanoma. Graham is assistant professor of pediatrics and immunology at the University of Colorado Denver School of Medicine.

To investigate this hypothesis, Graham's team performed
microarray analyses and found that MERTK was overexpressed in about 50%
of melanomas compared with normal human melanocytes. Moreover, there was higher
MERTK expression in metastatic melanoma than in primary tumors.

In human melanoma cell lines, a small molecule inhibitor
of MERTK decreased proliferation and invasion and increased apoptosis compared
with vehicle.

Mice injected with human melanoma cell lines pretreated
with MERTK small hairpin RNA developed smaller tumors than mice injected
with cells pretreated with a scrambled control shRNA. Graham said the team did
not test the small molecule in mouse models because it was not suitable for in
vivo work.

Additional in vitro studies revealed that MERTK
promoted growth, proliferation and survival in melanoma cells by activating at
least three signaling pathways, including the Ras/Raf/MEK/MAPK
signaling cascade (see"Downstream of MERTK").

"It is particularly noteworthy that the JCI
study showed 28% of brain metastases of melanoma had elevated MERTK
expression" because so little is known about how melanoma metastasizes to
the brain, said Keiran Smalley. He is assistant professor in the molecular
oncology program and scientific director of the Melanoma Research Center of
Excellence at the H. Lee Moffitt Cancer Center & Research Institute.

Better with BRAF?

The immediate
questions are whether a MERTK inhibitor can show efficacy in primary melanoma
tumors that have developed resistance to BRAF inhibitors-such as Zelboraf
vemurafenib-and
whether blocking MERTK will have additive effects in combination with
inhibitors of BRAF and MEK.

"One aspect that is not yet clear is the importance
of MERTK signaling relative to that of other driver oncogenes in melanoma,"
such as mutant BRAF and NRAS, Smalley said.

He noted that the JCI team showed that MERTK
knockdown "only delayed melanoma growth, making it likely that other
drivers are also involved in tumor progression."

Jennifer Low, group medical director at the Genentech Inc. unit of Roche, agreed that "studies
specifically looking at the prevalence of MERTK activation in the general
melanoma population and in patients with BRAF mutations would be of interest."

Smalley also wanted to know whether MERTK
expression was elevated in tumors from patients with melanoma in whom BRAF
inhibitors failed. "This possibility could be explored further by
determining whether MERTK expression mediates the increased MEK
signaling in melanoma cells that are resistant to BRAF inhibition," he
said.

Graham said previous studies by his group have shown
that MERTK expression plays a role in resistance to chemotherapy in
brain cancer4, lung cancer5 and acute lymphoblastic
leukemia (ALL),9,10 "and we are investigating whether this is
also the case in melanoma. We think that MERTK inhibition might help treat
melanoma that has developed resistance to BRAF inhibitors" and other
therapies.

However, Low pointed out that the JCI study did
not establish "whether inhibiting MERTK would reverse or delay progression
in melanoma if combined with, or used following, a BRAF inhibitor." Thus,
she wanted to see MERTK inhibition tested in cell lines and animal models of
BRAF mutation-positive melanoma that had developed resistance to BRAF
inhibitors.

Smalley agreed it would be important "to determine
whether the combination of MERTK and BRAF inhibitors gives a more durable
response to treatment than a BRAF inhibitor alone," as has been observed
with combined BRAF/MEK inhibition.

Graham said the team has developed a next-generation MERTK
inhibitor with better bioavailability than the molecule used in the published
study and is now testing it in combination with Zelboraf and an undisclosed MEK
inhibitor.

"We have found these combinations increased efficacy
in melanoma cell lines compared with monotherapy," he said. "Now we
plan to test the combinations in primary melanoma cells and mouse models of
melanoma" and expect to publish the results this year.

The team has conducted
follow-on studies to explore the therapeutic implications of another finding
from the JCI study: results of microarray analyses showing that more
than 50% of tumor-infiltrating macrophages highly expressed MERTK.

Indeed, Graham said the team has another paper in press
showing that MERTK inhibition-in addition to its direct effect on tumors-has an
immunomodulatory action in melanoma and other MERTK-expressing cancers.

"We think that the high levels of MERTK
expressed on tumor-infiltrating macrophages may increase their efficiency at
clearing apoptotic melanoma cells" and thus limit the time during which
antigens from those dying cells could trigger an immune response, Graham said.
Thus, MERTK inhibition could decrease macrophage-aided cell clearance and
thereby stimulate immune responses to the tumor, he said.

He added, "The immunomodulatory effect of MERTK
inhibition on macrophages could also be important in cancer types that
themselves do not overexpress MERTK."

The team also is collecting plasma serum from patients
with melanoma to determine whether circulating levels of soluble MERTK or GAS6
correlate with disease progression and is planning studies to better understand
the role of MERTK in cancer cell migration, invasion and metastasis, Graham
said.

The University of North Carolina at Chapel Hill has
patented the MERTK inhibitors and their therapeutic uses. The IP is available
for licensing.

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